The Herpes Virus Entry Mediator (HVEM or TNFRSF14) is a particularly interesting TNF receptor because it engages in diverse interactions, thereby acting as a molecular switch mediating pro-inflammatory or anti- inflammatory responses, depending on context. HVEM is unique in binding TNF molecules (LIGHT also known as TNFSF14) and immunoglobulin (Ig) super family members, BTLA and CD160. Furthermore, it is a signaling receptor, but also as a ligand for signaling by BTLA. Additionally, it can interact in Trans, i.e., between cells, but also in cis, because the same cell can express HVEM and one or more of its binding partners. We have found that HVEM plays a key role in controlling mucosal inflammation, both in colitis initiated by T cell transfer to Rag-/- mice and in Citrobacter rodentium infection, a model for attaching and effacing intestinal bacterial infections. In C. rodentium infection, both innate and adaptive responses are impaired in Hvem-/- mice, including decreased IL-22 production by specialized intestinal natural killer cells (NK22 cells) and decreased generation of IL-17 secreting T lymphocytes (Th17 cells). Here we propose experiments designed to reveal the underlying mechanisms for HVEM-mediated control of mucosal inflammation and bacterial clearance. Using mice with targeted mutations, we will determine the nature of the inflammatory, innate immune response in the absence of HVEM, and we will determine if increased inflammation is caused by decreased IL-22 synthesis. We will identify the critical binding partner(s) for HVEM in the mucosal innate response, and the cell types that must express HVEM and its partner. We will address similar questions in the adaptive mucosal immune response, namely the HVEM dependent cell types required for normal Th17 cell generation following infection, the relevant binding partner, and the cell type expressing it. Additionally, we will identify contexts in which the HVEM-BTLA cis complex is important in vivo, and we will determine if the decrease in colonic Th17 cells is due to increased apoptosis. HVEM is a key but under studied player in mucosal immunity, but our experimental results will untangle the network of HVEM-mediated interactions to reveal the means by which it regulates mucosal inflammation. PUBLIC HEALTH RELEVANCE: HVEM is a molecule related to tumor necrosis factor receptors, and we have made the novel finding that it plays an important role in controlling intestinal inflammation following bacterial infection or in an animal model of inflammatory bowel disease. The proposed experiments will determine how HVEM works to control the intestinal immune response, which may aid in developing therapeutics directed to HVEM or its binding partners to ameliorate intestinal inflammation.